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17q21.31 sub-haplotypes underlying H1-associated risk for Parkinsons disease are associated with LRRC37A/2 expression in astrocytes

By Kathryn R. Bowles, Derian A Pugh, Yiyuan Liu, Alan E Renton, Sara Bandres-Ciga, Ziv Gan-Or, Peter Heutink, Ari Siitonen, Sarah Bertelsen, Celeste M Karch, Steven Frucht, Brian H Kopell, Inga Peter, You Jeong Park, Gunter U Hoglinger, IPDGC, Alexander W Charney, Towfique Raj, John F Crary, Alison Goate

Posted 30 Nov 2019
bioRxiv DOI: 10.1101/860668

Parkinsons disease (PD) is genetically associated with the H1 haplotype of the MAPT 17q.21.31 locus, although the causal gene and variants underlying this association have not been identified. To better understand the genetic contribution of this region to PD, we fine-mapped the 17q21.31 locus in order to identify novel mechanisms conferring risk for the disease. We identified three novel H1 sub-haplotype blocks across the 17q21.31 locus associated with PD risk. Protective sub-haplotypes were associated with increased LRRC37A/2 copy number and expression in human brain tissue. We found that LRRC37A/2 is a membrane-associated protein that plays a role in cellular migration, chemotaxis and astroglial inflammation. In human substantia nigra, LRRC37A/2 was primarily expressed in astrocytes, interacted directly with soluble alpha-synuclein, and co-localized with Lewy bodies in PD brain tissue. These data indicate that a novel candidate gene, LRRC37A/2, contributes to the association between the 17q21.31 locus and PD via its interaction with alpha-synuclein and its effects on astrocytic function and inflammatory response. These data are the first to associate the genetic association at the 17q21.31 locus with PD pathology, and highlight the importance of variation at the 17q21.31 locus in the regulation of multiple genes other than MAPT and KANSL1, as well as its relevance to non-neuronal cell types.

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